DE19932796A1 - Diacylhydrazine derivatives - Google Patents

Abstract

Diacylhydrazine derivatives of general formula (I) wherein X, Y, Z, R<1>, R<2> and R<3> have the meanings cited in Claim 1, and the physiologically acceptable salts or solvates thereof, which are integrin inhibitors and can be used to combat thromboses, myocardial infarcts, coronary cardiac diseases, arteriosclerosis, inflammations, tumors, osteoporosis, infections and restenosis following angioplasty or during pathological processes that are maintained or propagated by angiogenesis.

Description

The invention relates to diacylhydrazine derivatives of the general formula I.

wherein
XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n - or

Z NR ² or CH-R ² R ¹ , R ² each independently of one another H or A,
R ³ H, Ar or Het,
R ⁴ H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO ₂ , CF ₃ or OCF ₃ ,
A alkyl with 1-6 C atoms,
Ar unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF ₃ , OCF ₃ , CN, NO ₂ or Hal, which is substituted by mono-, di- or triple by A, OH, OA, CF. ₃ , OCF ₃ , CN, NO ₂ or Hal substituted phenyl can be substituted in such a way that an unsubstituted or substituted biphenyl is formed,
Hal F, Cl, Br or I,
Het a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N and / or 1 or 2 S or O atoms may be present and the heterocyclic radical once or twice by CN , Hal, OH, OA, CF ₃ , A, NO ₂ or OCF ₃ can be substituted,
Het ^{1 is} a 5- or 6-membered aromatic heterocycle having 1 to 4 N atoms, which is unsubstituted or mono- or disubstituted by Hal, A, OA, Ar, OAr, arylalkyl, CN, NO ₂ , CF ₃ or OCF ₃ can be,
n 2, 3, 4, 5 or 6,
m, o represent 0, 1 or 2,
as well as their physiologically acceptable salts and solvates.

Partially similar compounds are known from EP 0 632 016, WO 97/26250, WO 97/24124 or DE 198 31 710 known.

The invention was based on the problem of new connections Find valuable properties, especially those that are used Manufacture of drugs can be used.

It has been found that the compounds of formula 1 and their salts good tolerance very valuable pharmacological properties have. Above all, they act as integrin inhibitors, whereby they especially the interactions of the αv, β3, β5 or β6 integrin Inhibit receptors with ligands, such as. B. the binding of fibrinogen the integrin receptor.

Integrins belong to the family of heterodimeric class I trans membrane receptors found in numerous cell matrix or cell-cell Adhesion processes play an important role (Tuckwell et al., 1996, Symp. Soc. Exp. Biol. 47). They can be roughly divided into three classes are: the β1 integrins, the receptors for the extracellular matrix represent the β2 integrins, which can be activated on leukocytes and are "triggered" during inflammatory processes, as well as the αv- Integrins that control the cell response in wound healing and other patholo processes (Marshall and Hart, 1996, Semin. Cancer  Biol. 7, 191). The relative affinity and specificity for ligand binding is achieved by combining the different α and β subunits certainly.

The compounds according to the invention show particular effectiveness in Case of the integrins αvβ1, αvβ3, αvβ5, αllβ3 as well as αvβ6 and αvβ8, preferred of αvβ3, αvβ5 and αvβ6, as well as αllbβ3.

αvβ6 is a relatively rare integrin (Busk et al., J. Biol. Chem. 1992, 267 (9), 5790), which multiplies during repair processes in epithelial tissue is formed and the natural matrix molecules fibronectin and tenascin preferentially binds (Wang et al., Am. J. Respir. Cell Mol. Biol. 1996, 15 (5), 664). The physiological and pathological functions of αvβ6 are not yet known exactly, but it is believed that this integrin at physiological processes and diseases (e.g. inflammation, Wound healing, tumors) involving epithelial cells, one plays an important role. Thus, αvβ6 is expressed on keratinocytes in wounds (Haapasalmi et al., J. Invest. Dermatol. 1996, 106 (1), 42), from which it can be assumed that in addition to wound healing processes and inflammation also other pathological events of the skin, such as. B. psoriasis Agonists or antagonists of said integrin can be influenced. Αvβ6 also plays a role in the respiratory epithelium (Weinacker et al., Am. J. Respir. Gell Mol. Biol. 1995, 12 (5), 547), so that corresponding Agonists / antagonists of this integrin in respiratory diseases such as bronchitis, Asthma, pulmonary fibrosis and respiratory tumors successfully used could become. Ultimately, it is known that αvβ6 is also an intestinal epithelium Role, so that corresponding integrin agonists / antagonists the treatment of inflammation, tumors and wounds of the Gastrointestinal tract could be used.  

It has been found that the compounds of the formula I and their salts as soluble molecules exert an effect on cells that the mentioned receptor, or if they are bound to surfaces, represent artificial ligands for αvβ6-mediated cell attachment. In front they all act as αvβ6 integrin inhibitors, in particular the Inhibit interactions of the receptor with other ligands, such as. B. the binding of fibronectin.

The compounds of the invention are particularly potent Inhibitors of the vitronectin receptor αvβ3.

The αvβ3 integrin is grown on a number of cells, e.g. B. endothelial cells, β Cells of the smooth vascular muscles, for example the aorta, cells for Degradation of bone matrix (osteoclasts) or tumor cells, expressed.

The effect of the compounds of the invention can, for. B. after the Method detected by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.

B. Felding-Habermann and D. A. Cheresh describe in Curr. Opin. Cell. Biol. 1993, 5, 864 the meanings of integrins as adhesion receptors for the most diverse phenomena and clinical pictures, especially in Regarding the vitronectin receptor αvβ3.

The dependence of the development of angiogenesis on the Interaction between vascular integrins and extracellular Matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 1994, 264, 569-571.

The possibility of inhibiting this interaction and thus to Initiation of apoptosis (programmed cell death) angiogenic vascular  Cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier and D. A. Cheresh in Cell 1994, 79, 1157-1164. There were z. B. αvβ3 antagonists or Antibodies to αvβ3 are described that cause tumor shrinkage by inducing apoptosis.

The experimental evidence that the invention Connections the attachment of living cells to the corresponding ones Prevent matrix proteins and, accordingly, the attachment of Preventing tumor cells from matrix proteins can be done in a cell adhesion test are provided, analogous to the method of F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.

PC Brooks et al. describe in J. Clin. Invest. 1995, 96, 1815-1822 α _v β ₃ - antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds can bind metal proteinases to integrins inhibit and thus prevent the cells from the enzymatic activity of Can use proteinals. One example is the inhibibility of the bond of MMP-2- (Matrix Metallo-Proteinase-2) to the Vitronectin Receptor Finding αvβ3 by a cyclo-RGD peptide as described in P.C. Brooks et al., Cell 1996, 85, 683-693.

The compounds of formula I according to the invention can therefore as Active pharmaceutical ingredients, in particular for the treatment of Tumor diseases, osteoporoses, osteolytic diseases as well used to suppress angiogenesis.  

Compounds of formula I, the interaction of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein IIb / IIIa) prevent GPIIb / IIIa antagonists from spreading tumor cells through metastasis. This is evidenced by the following observations:
The spread of tumor cells from a local tumor into the vascular system occurs through the formation of micro-aggregates (microthrombi) through the interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system. The micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIa / IIIb antagonists can be regarded as effective metastasis inhibitors.

In addition to binding fibrinogen, compounds of the formula I Fibronectin and the von Willebrand factor to the fibrinogen receptor Platelets also bind other adhesive proteins, such as Vitronectin, collagen and laminin, to the appropriate receptors the surface of different cell types. In particular, they prevent that Formation of platelet thrombi and can therefore be used for treatment of thrombosis, apoplexy, heart attack, inflammation and Arteriosclerosis can be used.

The antiplatelet effect can be demonstrated in vitro the method of Born (Nature 1962, 4832, 927-929).  

The invention relates to compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates as therapeutic agents.

The invention accordingly relates to compounds of the formula I. according to claim 1 and their physiologically acceptable salts and / or Solvate as integrin inhibitors.

The invention relates to compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for Application in fighting diseases.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used, especially for Prophylaxis and / or therapy of diseases of the circulatory system, Thrombosis, heart attack, arteriosclerosis, apoplexy, angina pectoris, Tumor diseases, such as tumor growth or tumor metastasis, osteolytic diseases such as osteoporosis, pathological angiogenic Diseases such as B. inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular Histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic Glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, Restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in acute kidney failure and in Wound healing to support the healing process.

The compounds of formula I can act as antimicrobials Substances are used in operations where biomaterials, Implants, catheters or pacemakers can be used.  

They have an antiseptic effect. The effectiveness of antimicrobial activity can be described by P. Valentin-Weigund et al. in infection and immunity, 1988, 2851-2855 described methods can be detected.

Since the compounds of formula I inhibitors of fibrinogen binding and so that ligands of the fibrinogen receptors on platelets represent can be used as diagnostics for the detection and localization of thrombi be used in vivo in the vascular system, for example, provided that be substituted by a radioactive or UV-detectable residue.

The compounds of the formula I can also be used as inhibitors of fibrinogen binding as effective tools for studying the metabolism of platelets in different activation stages or of intracellular signaling mechanisms of the fibrinogen receptor. The detectable unit of a "label" to be installed, e.g. B. isotope labeling by ³ H, allows to investigate the mechanisms mentioned after binding to the receptor.

It means below:
Ac = acetyl
Aza-Gly = H ₂ N-NH-COOH
BOC = tert-butoxycarbonyl
CBZ or Z = benzyloxycarbonyl
DCCI = dicyclohexylcarbodiimide
DCM = dichloromethane
DIPEA = diisopropylethylamine
DMF = dimethylformamide
EDCI = N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide
Et = ethyl
Fmoc = 9-fluorenylmethoxycarbonyl
Gly = glycine
HATU = O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
HOBt = 1-hydroxybenzotriazole
Me = methyl
MBHA = 4-methyl-benzhydrylamine
Mtr = 4-methoxy-2,3,6-trimethylphenylsulfonyl
NMP = N-methylpyrrolidone
NMR = nuclear magnetic resonance
HONSu = N-hydroxysuccinimide
OBzl = benzyl ester
OtBu = tert-butyl ester
Oct = octanoyl
OMe = methyl ester
OEt = ethyl ester
Pbf = 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
β-Phe = β-phenylalanine
POA = phenoxyacetyl
R _f value = retention factor
RP = reversed phase
RT = retention time
Sal = salicyloyl
TBTU = O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate
TFA = trifluoroacetic acid
Trt = trityl (triphenylmethyl).

The compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All these forms (e.g. D and L forms) and their mixtures (e.g. the DL- Forms) are included in Formula I.

In the compounds of claim 1 are also so-called prodrug derivatives included, d. H. with z. B. alkyl or Acyl groups, sugars or oligopeptides modified compounds of  Formula I, which in the organism quickly to the effective inventive Connections are split.

This also includes biodegradable polymer derivatives of the invention appropriate connections, as z. B. in Int. J. Pharm. 1995, 115, 61-67 is described.

In the compounds of claim 1 are also Derivatives of the compounds of formula I included the Carboxyl group in a pharmaceutically acceptable metabolically labile Ester or an amide thereof is converted.

Furthermore, free amino groups or free hydroxyl groups can be used as Substituents of compounds of formula I with corresponding Protecting groups.

Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. B. mono- or dihydrates or addition compounds with alcohols, such as. B. with methanol or ethanol. The invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that

• a) for the preparation of a compound of the formula I in which Z is NR ² , a compound of the formula II,
  in which X, Y, R ¹ and R ^{2 have} the meanings given in claim 1, and in which free amino groups are protected by a suitable amino protecting group,
  with a compound of formula III
  in which R ² and R ^{3 have} the meanings given in claim 1 and in which a free hydroxyl group is protected by a suitable hydroxyl protective group or is bound to a solid phase,
  implements
  and then removing the protecting groups and / or the solid phase,
  or
• b) a compound of the formula IV,
  in which X and Y have the meanings given in claim 1, and in which free amino groups are protected by a suitable amino protecting group,
  with a compound of formula V
  in which R ¹ , R ² , R ³ and Z have the meanings given in claim 1, and in which a free hydroxyl group is protected by a suitable hydroxyl protective group or is bound to a solid phase,
  implements
  and then removing the protecting groups and / or the solid phase;
  or
• c) liberates a compound of formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.

For the entire invention applies that all residues that occur several times, such as. B. R ^{2 may be the} same or different, ie are independent of each other.

In the above formulas, A means alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, n = butyl, isobutyl, sec-butyl or tert-butyl, furthermore also n-pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl; 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl- 2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.
Methyl is particularly preferred for A.

Amino protecting group preferably means acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbo benzoxy"), 4-methoxybenzyloxycarbonyl, Fmoc, Mtr or benzyl.
Fmoc is particularly preferred.

Ar preferably denotes unsubstituted phenyl, further preferably mono-, di- or tri-substituted phenyl by A, OH, OA, CF ₃ , OCF ₃ , CN, NO ₂ or Hal, which is likewise substituted by one, two or three times by A, OH, OA, CF ₃ , OCF ₃ , CN, NO ₂ or Hal substituted phenyl can be substituted in such a way that an unsubstituted or substituted biphenyl is formed. A and Hal have the preferred or particularly preferred meanings given above or below.

Ar therefore preferably means phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p Isopropytphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p- Hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m-, p-trifluoromethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m-, p-nitrophenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- Dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-ditrifluoromethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- Ditrifluoromethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihnitrophenyl,  2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6- , 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl. Furthermore, however, preference is also given to unsubstituted biphenyl or substituted biphenyl, in particular preferably 4-biphenyl or 3-biphenyl, 4 '- (2-methyl-biphenyl), 4' - (3-methyl-biphenyl), 4 '- (4-methyl-biphenyl), 3' - (2- Methyl-biphenyl), 3 '- (3-methyl-biphenyl), 3' - (4-methyl-biphenyl), 4- (2- Methyl-biphenyl), 4- (3-methyl-biphenyl), 3- (2-methyl-biphenyl), 3- (4-methyl biphenyl), 4 '- (2-fluoro-biphenyl), 4' - (3-fluoro-biphenyl), 4 '- (4-fluoro-biphenyl), 3 '- (2-fluorobiphenyl), 3' - (3-fluorobiphenyl), 3 '- (4-fluorobiphenyl), 4- (2-fluorine biphenyl), 4- (3-fluoro-biphenyl), 3- (2-fluoro-biphenyl) or 3- (4-fluoro biphenyl).

Ar particularly preferably denotes phenyl, p-chlorophenyl, 3,5- Dichlorophenyl, m-nitrophenyl or 4 '- (4-fluorobiphenyl).

Arylalkyl preferably means benzyl, phenylethyl, phenylpropyl or Naphthylmethyl, particularly preferably benzyl.

Hal is preferably F, Cl or Br.

Het means a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, it being possible for 1 or 2 N and / or 1 or 2 S or O atoms to be present and the heterocyclic radical to be one or two times CN, Hal, OH, OA, CF ₃ , A, NO ₂ or OCF ₃ can be substituted.

Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-  Pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or-5-yl, 1,2,4- Triazol-1-, -4 or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl 1,2,4-oxadiazol-3- or-5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4- Thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6- 2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, Pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7- Benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or 5- Benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7- Benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7- Benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz- 2,1,3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also partially or be fully hydrogenated. Het can also mean 2,3-dihydro-2-, 3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, 2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1 H-indolyl, 2,3- Dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4- pyrazolyl, 1,4-dihydro-1-, -2-, -3-or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, 3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or -6- pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxane 2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3- piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- 6-, -7- or 8-isoquinolinyl.  

Het 2-, 3- or 4-pyridyl or 1-, 2-, 3-, 4-, 5-, 6- is particularly preferred or 7-1H-indolyl.

Het ¹ denotes a 5- or 6-membered aromatic heterocycle having 1 to 4 N atoms, which is unsubstituted or mono- or disubstituted by Hal, A, OA, Ar, OAr, arylalkyl, CN, NO ₂ , CF ₃ or OCF ₃ may be substituted, wherein Hal, A, arylalkyl and Ar has one of the meanings given above.

Het ¹ is preferably unsubstituted or substituted 2- or 3-pyrrolyl, 2, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3- or 4-pyridazinyl, 2- or 3-pyrazinyl. Pyridin-2-yl or 4-methyl-pyridin-2-yl is particularly preferred.

Het ¹ -NH is preferably pyrrol-2 or pyrrol-3-ylamine, imidazol-2, imidazol-4 or imidazol-5-ylamine, pyrazol-3, pyrazol-4 or pyrazol-5-ylamine, pyridyl -2-, pyridyl-3- or pyridyl-4-ylamine, pyrimidin-2-, pyrimidin-4-, pyrimidin-5- or pyrimidin-6-ylamine, pyridazin-3 or pyridazin-4-ylamine, pyrazin-2 - or pyrazin-3-ylamine, where the heterocyclic rings mentioned can be substituted by preferably alkyl. Pyridyl-2-ylamine or 4-methyl pyridin-2-ylamine is particularly preferred for Het ¹ -NH.

OA preferably means methoxy, ethoxy, propoxy or butoxy, furthermore also pentytoxy or hexyloxy.

R ¹ is preferably H or A, where A has one of the meanings given above; especially H.

R ² is preferably H or A, where A has one of the meanings given above; especially H.

R ³ preferably denotes H, Ar or Het, where Ar and Het have one of the meanings given above; in particular phenyl, p-chlorophenyl, 3,5-dichlorophenyl, m-nitrophenyl or 4 '- (4-fluorobiphenyl).

R ⁴ preferably denotes H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO ₂ , CF ₃ or OCF ₃ , where A, arylalkyl, Ar and Hal have one of the meanings given above; especially H and methyl.

X denotes H ₂ NC (= NH) -NH- or Het ¹ -NH, where Het ¹ -NH has one of the meanings given above; in particular XH _{2 means} NC (= NH) - NH- or 4-methyl-pyridin-2-ylamine.

Y means - (CH ₂ ) _n or

where n is 2, 3, 4, 5 or 6, in particular 4 and m is 0, 1 or 2, in particular 0 and o is 0, 1 or 2, in particular 0 and R ^{4 has} one of the meanings given above.

Z represents NR ² or CH-R ² , where R ^{2 has} one of the meanings given above, in particular NH or CH ₂ .

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ip, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia) means XH ₂ NC (= NH) -NH-,
in Ib) Y

means
in Ic) Z means NR ² ,
in Id) Z means GH-R ² ,
in Ie) XH ₂ NC (= NH) -NH- or Het ¹ -NH- and
Y - (CH ₂ ) _n - means
in If) XH ₂ NC (= NH) -NH- and
Y

means
in Ig) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n ,
R ³ ares,
Z NH means
in Ih) XH ₂ NC (= NH) -NH-,
R ³ ares,
Z NH and
Y

means
in li) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
R ³ ares,
Y - (CHZ) _n and
Z means CH ₂
in Ik) XH ₂ NC (= NH) -NH-,
R ³ ares,
Z CH ₂ and
Y

means
in Im) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n - or

Z NH or CH ₂ ,
R ¹ , R ² H,
R ³ ares,
R ⁴ H,
Het ¹ 4-methyl-pyridin-2-yl,
n 4 and
m, o means 0.
in In) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) or

Z NH,
R ¹ , R ² H,
R ^{3 is} phenyl which is unsubstituted or mono-, di- or trisubstituted by NO ₂ or Hal, which can be substituted by phenyl mono-, di- or trisubstituted by Hal in such a way that an unsubstituted or substituted biphenyl is formed,
R ⁴ H,
Het ¹ 4-methyl-pyridin-2-yl,
n 4 and m, o means 0,
in lo) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n or

Z CH ₂ ,
R ¹ , R ² H,
R ⁴ H,
R ^{3 is} phenyl which is unsubstituted or mono-, di- or trisubstituted by NO ₂ or Hal, which can be substituted by phenyl mono-, di- or trisubstituted by Hal in such a way that an unsubstituted or substituted biphenyl is formed,
Het ¹ 4-methyl-pyridin-2-yl,
n 4 and
m, o means 0
in Ip) XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n - or

Z NH or CH ₂ ,
R ¹ , R ² H,
R ⁴ H,
R ^{3 is} phenyl which is unsubstituted or mono-, di- or trisubstituted by NO ₂ or shark, which may be substituted by phenyl mono-, di- or trisubstituted by Hal in such a way that an unsubstituted or substituted biphenyl is formed,
Het ¹ 4-methyl-pyridin-2-yl,
n 4 and
m, o means 0.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart; ) are described, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

Compounds of formula I can preferably under the conditions a peptide synthesis can be obtained. You work appropriately  by conventional methods of peptide synthesis, such as. B. in Houben-Weyl, 1.c., volume 15 / II, pages 1 to 806 (1974).

The direct precursors of the compounds of formula I can also, for. B. according to Merrifield (Angew. Chem. 97, 801-812 1985) on a solid phase, e.g. B. a swellable polystyrene resin.

As a solid phase, in principle, all carriers, as z. B. from the Solid-phase peptide chemistry or nucleic acid synthesis are known be used.

Polymeric solid phases are also suitable as polymeric carrier materials preferably hydrophilic properties, for example cross-linked Poly sugar such as cellulose, Sepharose or Sephadex®, acrylamides, Polyethylene glycol-based polymer or Tentakelpolymers®. Preferably, the solid phase is trityl chloride polystyrene resin, 4- Methoxytritylchloride resin, Merrifield resin and Wang resin used.

Thus compounds of formula I can be obtained by using a Reacting compound of formula II with a compound of formula III, and then removing the protecting groups or the solid phase.

The compounds of formula I can also be obtained by to obtain a compound of formula IV with a compound of formula V implemented, and then removed the protective groups.

The coupling reaction is preferably carried out in the presence of a Dehydrating agent, e.g. B. a carbodiimide such as DCCI or EDCI, further z. B. propanephosphonic anhydride (cf. Angew. Chem. 1980, 92, 129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2- dihydroquinoline, in an inert solvent, e.g. B. a halogenated Hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as Acetonitrile, in dimethyl sulfoxide or in the presence of these solvents  Temperatures between about -10 and 40, preferably between 0 and 30 °. To the intramolecular cyclization before the intermolecular To promote peptide binding, it is appropriate to in dilute solutions work.

The response time is between depending on the conditions used a few minutes and 14 days.

Instead of compounds of the formula II and / or IV, derivatives can also be used of compounds of formula II and / or IV, preferably one before activated carboxylic acid, or a carboxylic acid halide, a sym metric or mixed anhydride or an active ester used become. Such residues for activation of the carboxy group in typical Acylation reactions are described in the literature (e.g. in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart;) described.

Activated esters are conveniently formed in situ, e.g. B. by adding HOBt or N-hydroxysuccinimide.

The reaction is usually carried out in an inert solvent Use of a carboxylic acid halide in the presence of a acid-binding agent, preferably an organic base such as Triethylamine, dimethylaniline, pyridine or quinoline.

Also the addition of an alkali or alkaline earth metal hydroxide or catbonate or bicarbonate or other salt of a weak acid Alkali or alkaline earth metals, preferably of potassium, sodium, Calcium or cesium can be beneficial.

The compounds of the formula I can also be obtained by to get them from their functional derivatives by solvolysis, in particular Hydrolysis, or released by hydrogenolysis.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, in particular those which have a instead of an HN group Wear SG ¹ -N group, in which SG ^{1 represents} an amino protective group and / or those which carry a hydroxy protective group instead of the H atom of a hydroxy group, e.g. B. those which correspond to the formula I, but instead of a group -COOH carry a group -COOSG ² , in which SG ^{2 is} a hydroxy protective group.

Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material his. If the existing protecting groups are different from each other, they can be split off selectively in many cases (see: T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 or P. J. Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart-New-York, 1994, H. Kunz, H. Waldmann in Comprehensive Organic Synthesis, Vol. 6 (ed. B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon, Oxford, 1991, pp. 631-701).

The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical Protect (block) implementations. Typical for such groups are in particular unsubstituted or substituted acyl, aryl, Aralkoxymethyl or aralkyl groups. Since the amino protecting groups after the desired reaction (or sequence of reactions) is removed Type and size otherwise not critical; however, those are preferred with 1-20 C atoms. The term "acyl group" is related to to understand the present procedure in the broadest sense. He surrounded by aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids Acyl groups and in particular alkoxycarbonyl, alkenyloxycarbonyl, Aryloxycarbonyl and especially aralkoxy-carbonyl groups. examples for  such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, Ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (Aloc), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitro benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (Phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc) or Arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred Amino protecting groups are Boc, Fmoc and Aloc, furthermore Z, benzyl and Acetyl.

The term "hydroxy protecting group" is also well known and refers to groups that are suitable for a hydroxy group to protect chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, Aroyl or acyl groups, furthermore also alkyl groups, alkyl, aryl or Aralkylsilyl groups or O, O- or O, S-acetals. The nature and size of the Hydroxy protecting groups are not critical as they are the desired ones chemical reaction or reaction sequence are removed again; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples for hydroxy protecting groups are u. a. Aralkyl groups such as benzyl, 4- Methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, Alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.- Butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene, Cyclopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene or o, p-Dimethoxybenzylidenacetal, acyclic acetals such as tetrahydropyranyl  (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), Benzyloxymethyl (BOM) or methylthiomethyl (MTM). Especially preferred hydroxyl protective groups are benzyl, acetyl, tert-butyl or TBS.

The liberation of the compounds of formula I from their functional derivatives is from the Literature known (e.g. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 or P. J. Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgart-New-York, 1994). It is also possible to do so from those known per se, but not here make use of the variants mentioned.

A base of formula I can with an acid in the associated Acid addition salt are transferred, for example by reaction equivalent amounts of the base and the acid in an inert Solvents such as ethanol and subsequent evaporation. For this Implementation include acids that are physiological deliver safe salts. So inorganic acids can be used be, e.g. B. sulfuric acid, sulfurous acid, dithionic acid, Nitric acid, hydrohalic acids such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as. B. orthophosphoric acid, Sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic one or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. formic acid, Acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, Hexadecanoic acid, octadecanoic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or  Ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, Adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, Chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, Glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, Cyclohexane carboxylic acid, glucose-1-phosphate, naphthalene mono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically not harmless acids, e.g. B. picrates, can be used for insulation and / or Purification of the compounds of formula I can be used. On the other hand, compounds of the formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, especially alkali metal or alkaline earth metal or in the corresponding ammonium salts are converted. As salts substituted ammonium salts, e.g. B. the dimethyl, diethyl or diisopropylammonium salts, monoethanol, diethanol or Diisopropylammonium salts, cyclohexyl, dicyclohexylammonium salts, Dibenzylethylenediammoniumsalze, further z. B. salts with arginine or Lysine.

The invention further relates to the use of the compounds of Formula I and / or their physiologically acceptable salts for Manufacture of a pharmaceutical preparation.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts or solvates, which in particular be produced non-chemical ways. Here, the Compounds of the formula I together with at least one solid liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more other active ingredients appropriate dosage form are brought.  

These preparations can be used as medicinal products in human or Veterinary medicine can be used. Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and with the new Compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, Dragees, capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use Solutions, preferably oily or aqueous solutions, furthermore Suspensions, emulsions or implants, for topical use Ointments, creams or powder. The new connections can too lyophilized and the resulting lyophilizates z. B. for the production of Injectables are used. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, Stabilizing and / or wetting agents, emulsifiers, salts for influencing of osmotic pressure, buffer substances, color, taste and / or contain several other active ingredients, e.g. B. one or more Vitamins.

For the application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (e.g. CO ₂ or chlorofluorocarbons). The active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol. Inhalation solutions can be administered using standard inhalers.

The compounds of formula I and their physiologically acceptable Salts can act as integrin inhibitors in fighting diseases, especially thrombosis, heart attack, coronary heart disease, Arteriosclerosis, tumors, osteoporosis, inflammation and infection be used.

The compounds of formula I according to claim 1 and / or their Physiologically acceptable salts are also used pathological processes that entertain through angiogenesis or are propagated, especially in tumors or rheumatoid arthritis.

The substances according to the invention are generally in Analogy to other known, commercially available peptides, but especially in analogy to that in US-A-4-472,305 described compounds administered, preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.01 and 2 mg / kg body weight. The special dose for everyone However, patients depend on a variety of factors for example on the effectiveness of the special used Connection, age, body weight, general health, Gender, the diet, the time and route of administration, the Elimination rate, drug combination and severity of respective disease to which the therapy applies. The parenteral Application is preferred.

Furthermore, the compounds of formula I as integrin ligands for Manufacture of columns for affinity chromatography Pure representation of integrins can be used.  

The ligand, i.e. H. a compound of formula I is an anchor function, e.g. B. the carboxy group of Asp on a polymeric support covalently coupled.

The manufacture of materials for affinity chromatography Integrin cleaning takes place under conditions such as those for condensation of amino acids are common and known per se.

The compounds of formula I contain one or more chiral centers and can therefore be in racemic or optically active form. Racemates obtained can be mecha by methods known per se nisch or chemically separated into the enantiomers. Preferably are from the racemic mixture by reaction with a optically active release agent diastereomers formed. Suitable as a release agent z. B. optically active acids, such as the D and L forms of tartaric acid, Diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, milk acid or the various optically active camphorsulfonic acids such as β- Camphorsulfonic acid. Enantiomer separation with is also advantageous With the help of an optically active release agent (e.g. dinitrobenzoyl phenylglycine) filled column; as a solvent is z. B. a mixture Hexane / isopropanol / acetonitrile, e.g. B. in a volume ratio of 82: 15: 3.

Of course, it is also possible to use optically active compounds of the formula I. according to the methods described above, by choosing Aus used materials that are already optically active.

All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on the constitution of the End product to pH values between 2 and 10, extracted with Ethyl acetate or dichloromethane, separates, dries the organic phase  over sodium sulfate, evaporated and purified by chromatography Silica gel and / or by crystallization.

RT = retention time (minutes) with HPLC in the following systems:
Columns from Omnicrom YMC:

• 1. 4.6 × 250 mm, 5 μm, C ₁₈ (analysis);
• 2. 30 × 250 mm, 7 µm, C ₁₈ (preparation).

Gradients of acetonitrile (B) with 0.1% TFA and water (A) with 0.1% TFA are used as eluents (details in volume percent of acetonitrile). Retention time RT was at a flow of 1 ml / min. determined
Detection at 220 nm.

The diastereomers are preferably separated under the stated conditions.
Mass spectrometry (MS):
ESI (electrospray ionization) (M + H) ⁺
FAB (Fast Atomic Bombardment) (M + H) ⁺ .

example 1 1. 5- (9H-Fluoren-9-ylmethoxy) -3H- [1,3,4] oxadiazol-2-one

2 equivalents of phosgene (1.89M in toluene; 4.2 ml) are added to a solution of 3.91 mmol of hydrazinecarboxylic acid 9H-fluoren-9-yl methyl ester in 40 ml of dichloromethane and 40 ml of saturated aqueous NaHCO ₃ solution. After stirring for 15 minutes, the mixture is worked up in the customary manner and 5- (9H-fluoren-9-ylmethoxy) -3H- [1,3,4] oxadiazol-2-one ("AB") is obtained.

58 mg; IR (KBr): 3300 s, 1780 s, 1650 s, 1451 m, 1426 m, 1347 m, 1224 m, 918 m, 758w, 740 m cm ^-1 .

2. Resin-bound Fmoc-β-Phe-OH ("BC")

2.0 g of trityl chloride polystyrene resin (1.8 mmol theoretical loading) is washed in 20 ml of DMF. Then the resin is mixed with a solution of 2.7 mmol of Fmoc-β-Phe-OH and 2.25 mmol of DIPEA in 20 ml of DMF, shaken for 2 hours at room temperature and then 1 ml of methanol is added. Wash with DCM (5 × 20 ml) and methanol (3 × 20 ml) and dry.

3. Resin-bound Fmoc-azaGly-β-Phe ("CD")

0.48 mmol / g "BC" is with DCM (2 × 7 ml) and with NMP (1 y 7 ml) washed and then twice with 20% piperidine in 7 ml DMF first 5 min. and then 15 min. deprotects. The deprotected resin will washed with NMP (5 × 7 ml) and absolute DCM (5 × 7 ml) and with a solution of 0.72 mmol "AB" in 7 ml DCM and 90 min. at Shaken at room temperature.  

Wash with DCM (5 × 7 ml) and NMP (5 × 7 ml) and dry the resin.

4. 3- [4- (3-guanidionobenzoyl) semicarbazido] -3-phenylpropionic acid

0.24 mmol "CD" is washed with NMP (7 × 5 ml) and twice with 20% Piperidine in 7 ml DMF initially 5 min. and then 15 min. deprotects. The resin is then washed with NMP (5 × 7 ml) and DMF (2 × 7 ml) washed and washed with a solution of 0.48 mmol 3- (9H-fluorene-9- ylmethoxycarbonylamino) benzoic acid, 0.48 mmol HATU and 2.4 mmol Collidine in 5 ml DMF and 90 min. shaken at room temperature. You wash and deprotect as described.

The resin is then washed with a solution of 2.4 mmol N, N'-bis-BOC- 1-guanylpyrazole ("DE") in 4 ml of chloroform and 16 hours at 50 ° leave. It is washed with DCM, methanol and diethyl ether.

To split off the BOC groups, the resin is initially mixed with a mixture of 95% TFA and 5% trüsopropylsilane (5 ml) at room temperature for 90 min. and then 30 min. shaken. Removal of the solvent and cleaning with preparative RP-HPLC yields 3- [4- (3-guanidionobenzoyl) - semicarbazido] -3-phenylpropionic acid, trifluoroacetate.
RT = 19.1 (0 → 50% B, 30 min.)
MS (ESI): m / z = 385.1 ([M + H] ⁺ ).

Example 2

1. Analogously to Example 1, reaction of "CD" with 3- (9H-fluoren-9-ylmethoxycarbonylamino) phenylacetic acid, followed by cleavage of the Fmoc group and reaction with "DE" and cleavage of the BOC group and from the resin
3- [4- (3-guanidionophenylacetyl) semicarbazido] -3-phenylpropionic acid, trifluoroacetate.
RT = 4.3 (10 → 50% B, 30 min.)
MS (ESI): m / z = 399.1 ([M + H] ⁺ ).

2. Analogously to Example 1, one obtains by reacting "EF", produced by reacting "AB" with resin-bound Fmoc-protected p- (4-chlorophenyl) alanine

with 3- (9H-fluoren-9-ylmethoxycarbonylamino) benzoic acid, followed by cleavage of the Fmoc group and reaction with "DE" and cleavage of the BOC group and from the resin
3- [4- (3-Guanidionophenylacetyl) semicarbazido] -3- (4-chlorophenyl) propionic acid, trifluoroacetate.
RT = 22.8 (0 → 50% B, 30 min.)
MS (ESI): m / z = 419.0 ([M + H] ⁺ ).

Example 3

0.24 mmol "CD" is washed with NMP (7 × 5 ml) and twice with 20% Piperidine in 7 ml DMF initially 5 min. and then 15 min. deprotects.  

The resin is then washed with NMP (5 × 7 ml) and DMF (2 × 7 ml) washed and washed with a solution of 0.48 mmol 3- (9H-fluorene-9- ylmethoxycarbonylamino) valeric acid, 0.48 mmol HATU and 2.4 mmol Collidine in 5 ml DMF and 90 min. shaken at room temperature. You wash and deprotect as described.

The resin is then washed with a solution of 2.4 mmol N, N'-bis-BOC- 1-guanylpyrazole ("DE") in 4 ml of chloroform and 16 hours at 50 ° leave. You wash with DCM.

To split off the BOC groups, the resin is initially mixed with a mixture of 95% TFA and 5% triisopropylsilane (5 ml) at room temperature for 90 min. and then 30 min. shaken. Removal of the solvent and cleaning with preparative RP-HPLC yields 3- [4- (3-guanidionopentanoyl) semicarbazido] -3-phenylpropionic acid, trifluoroacetate.
RT = 18.2 (0 → 50% B, 30 min.)
MS (ESI): m / z = 365.1 ([M + H] ⁺ ).

Example 4

Analogously to Example 3, reaction of "EF" with 3- (9H-fluoren-9-ylmethoxycarbonylamino) valeric acid, followed by cleavage of the Fmoc group and reaction with "DE" and cleavage of the BOC group and from the resin
3- [4- (3-Guanidionopentanoyl) semicarbazido] -3- (4-chlorophenyl) propionic acid, trifluoroacetate.
RT = 21.9 (0 → 50% B, 30 min.)
MS (ESI): m / z = 399.1 ([M + H] ⁺ ).

Example 5

0.60 mmol "EF" is washed with 20 ml NMP and twice with 20% piperidine in 20 ml DMF for 5 min. and then 15 min. deprotects. The resin is then washed with NMP (5 × 20 ml) and DMF (2 × 20 ml) and with a solution of 0.90 mmol of N- (2- (4-methylpyridyl) -5- aminovaleric acid, 0.90 mmol of HATU and 6.0 mmol of collidine in 5 ml of DMF and shaken overnight at room temperature, washed with DMF, NMP and DCM. To separate from the solid phase, the washed resin is shaken with 20 ml of a mixture of DCM / acetic acid / trifluoroethanol (3: 1: 1) at room temperature, first 90 minutes and then 30 minutes.
Removal of the solvent gives 3- {4- [5- (4-methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (4-chlorophenyl) propionic acid, acetate.
RT = 19.3 (10 → 60% B, 30 min.)
MS (ESI): m / z = 448.1 ([M + H] ⁺ ).

Example 6

1. Analogously to Example 5, by reacting "FG", prepared by reacting "AB" with resin-bound Fmoc-protected β- (3,5-dichlorophenyl) alanine,

with N- (2- (4-methylpyridyl) 5-aminovaleric acid and cleavage from the resin
3- {4- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (3,5-dichlorophenyl) propionic acid, acetate.
RT = 19.3 (0 → 60% B, 30 min.)
MS (ESI): m / z = 483.4 ([M + H] ⁺ ).

2. Analogously to Example 5, by reacting "GH", prepared by reacting "AB" with resin-bound Fmoc-protected β- (3-nitrophenyl) alanine,

with N- (2- (4-methylpyridyl) 5-aminovaleric acid and cleavage from the resin
3- {4- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (3-nitrophenyl) propionic acid, acetate.
RT = 14.9 (0 → 60% B, 30 min.)
MS (ESI): m / z = 459.5 ([M + H] ⁺ ).

3. Analogously to Example 5, by reacting "HK", prepared by reacting "AB" with resin-bound Fmoc-protected β- (4-fluorophenyl) phenylalanine,

with N- (2- (4-methylpyridyl) 5-aminovaleric acid and cleavage from the resin
3- {4- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (4'- (4-fluoro) biphenyl) propionic acid, acetate.

4. Analogously to Example 5, by reacting "KL", prepared by reacting "AB" with resin-bound Fmoc-protected β- (2-nitrophenyl) alanine,

with N- (2- (4-methylpyridyl) 5-aminovaleric acid and cleavage from the resin
3- {4- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (2-nitrophenyl) propionic acid, acetate.
RT = 14.7 (0 → 60% B, 30 min.)
MS (ESI): m / z = 459.5 ([M + H] ⁺ ).

5. Analogously to Example 5, by reacting "LM", prepared by reacting "AB" with resin-bound Fmoc-protected β- (4-trifluoromethoxyphenyl) alanine,

with N- (2- (4-methylpyridyl) 5-aminovaleric acid and cleavage from the resin
3- {4- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (4-trifluoromethoxyphenyl) propionic acid, acetate.
RT = 19.8 (0 → 60% B, 30 min.)
MS (ESI): m / z = 498.5 ([M + H] ⁺ ).

Example 7

Analogously to Example 1.2, the resin "LM" is obtained by reacting trityl chloride polystyrene resin with Fmoc-protected 3-aminopropionic acid.

which deprotects analogously to example 1.3 and with "AB" to "MN"

is implemented.

"MN" is reacted with N- (2- (4-methylpyridyl) -5- aminovaleric acid as in Example 5. After splitting off the resin, 3- {4- [5- (4-methylpyridin-2-ylamino) is obtained. -pentanoyl] -semicarbazido} -3-propionic acid, acetate.
RT = 7.3 (0 → 60% B, 30 min.)
MS (ESI): m / z = 338.4 ([M + H] ⁺ ).

Example 8 1. 3-phenylglutaric anhydride

10 mmol of 3-phenylglutaric acid and 30 mmol of acetic anhydride are heated under reflux until completely dissolved. After cooling, 3 ml of diethyl ether are added, the precipitate is filtered off and washed with diethyl ether. 3-Phenylglutaric anhydride is obtained.
¹ H-NMR (250 MHz, CDCl ₃ ): δ = 2.85 (dd, 2H, CH (HCH) ₂ ), 3.1 (dd, 2H, CH (HCH) ₂ ), 3.4 (m, 1H, CH (CH ₂ ) ₂ ), 7.15-7.45 (m, 5H, aromatic H).

2. 5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3-phenyl pentanoic acid

2.0 mmol of 3-phenylglutaric anhydride and 2.0 mmol of Fmoc hydrazine are dissolved in 30 ml of THF and heated under reflux for 16 hours. The product is then extracted with 50 ml of DCM and 50 ml of 1N HCl solution, the organic phase is dried with MgSO ₄ and filtered off. After removing the solvent, 5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3-phenylpentanoic acid is obtained.
RT = 10.4 (30 → 80% B, 30 min); MS (ESI): m / z = 910.8 ([2M + Na] ⁺ ).

3. 5- [N '- (3-guanidino-benzoyl) hydrazino] -5-oxo-3-phenylpentanoic acid

5- [N '- (9H-Fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3-phenylpentanoic acid is deprotected analogously to that described in Example 1. A solution of 2.0 mmol of N, N'-bis-BOC-1-guanylpyrazole ("DE") in 4 ml of chloroform is then added to the deprotected compound and the mixture is left at 50 ° for 16 hours. The solvent is removed in vacuo. To split off the BOC groups, a mixture of 95% TFA and 5% triisopropylsilane (5 ml) is initially at room temperature for 90 min. and then 30 min. touched. Removal of the solvent and cleaning with preparative RP-HPLC gives 5- [N '- (3-guanidino-benzoyl) hydrazino] -5-oxo-3-phenylpentanoic acid, trifluoroacetate.
RT = 17.0 (10 → 50% B, 30 min.)
MS (ESI): m / z = 384.1 ([M + H] ⁺ ).

Example 9

1. Analogously to Example 5, reaction of 5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3-phenylpentanoic acid is obtained
with N- (2- (4-methylpyridyl) 5-aminovaleric acid
4- {N '- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] hydrazinocarbonyl} -3-phenylbutyric acid, acetate.
RT = 22.1 (10 → 60% B, 30 min.)
MS (ESI): m / z = 413.1 ([M + H] ⁺ ).

2. Analogously to Example 5, reaction of (3R) -5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3- (4-chlorophenyl) pentanoic acid is obtained
with N- (2- (4-methylpyridyl) 5-aminovaleric acid
(3R) -4- / N '- [5- (4-methyl-pyridin-2-ylamino) pentanoyl] hydrazinocarbonyl} -3- (4-chlorophenyl) butyric acid, acetate.
MS (FAB): m / z = 447.9 ([M + H] ⁺ ).

Example 10

Analogously to Example 3, reaction of 5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxo-3- (4-chlorophenyl) pentanoic acid is obtained
with 3- (9H-fluoren-9-ylmethoxycarbonylamino) valeric acid, subsequent elimination of the Fmoc group and reaction with "DE" and elimination of the BOC group
4- [N '- (5-guanidino-pentanoyl) hydrazinocarbonyl] -3-phenyl butyric acid, trifluoroacetate.
RT = 19.4 (0 → 50% B, 30 min.)
MS (ESI): m / z = 364.2 ([M + H] ⁺ ).

Example 11

Analogously to Example 5, reaction of 5- [N '- (9H-fluoren-9-ylmethoxycarbonyl) hydrazino] -5-oxopentanoic acid, prepared analogously to Example 8.2, from reaction of glutaric anhydride with Fmoc hydrazine,
with N- (2- (4-methylpyridyl) -5-aminovaleric acid
4- {N '- [5- (4-Methyl-pyridin-2-ylamino) pentanoyl] hydrazinocarbonyl} butyric acid, acetate.
MS (ESI): m / z = 337.4 ([M + H] ⁺ ).

The following examples relate to pharmaceutical preparations:

Example A Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses,  lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double distillation Water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg talc and 0.1 kg magnesium stearate is added in the usual way Tablets pressed in such a way that each tablet contains 10 mg of active ingredient.

Example F Dragees

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.  

Example G Capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 l of isotonic NaCl solution and fills the solution into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. A spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (10)

1. Compounds of formula I.
wherein
XH ₂ NC (= NH) -NH- or Het ¹ -NH-,
Y - (CH ₂ ) _n - or
Z NR ² or CH-R ²
R ¹ , R ² each independently of one another H or A,
R ³ H, Ar or Het,
R ⁴ H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO ₂ , CF ₃ or OCF ₃ ,
A alkyl with 1-6 C atoms,
Ar unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF ₃ , OCF ₃ , CN, NO ₂ or Hal, which is substituted by mono-, di- or triple by A, OH, OA, CF. ₃ , OCF ₃ , CN, NO ₂ or Hal substituted phenyl can be substituted in such a way that an unsubstituted or substituted biphenyl is formed,
Hal F, Cl, Br or I,
Het a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N and / or 1 or 2 S or O atoms may be present and the heterocyclic radical once or twice by CN , Hal, OH, OA, CF ₃ , A, NO ₂ or OCF ₃ can be substituted,
Het ^{1 is} a 5- or 6-membered aromatic heterocycle having 1 to 4 N atoms, which is unsubstituted or mono- or disubstituted by Hal, A, OA, Ar, OAr, arylalkyl, CN, NO ₂ , CF ₃ or OCF ₃ can be,
n 2, 3, 4, 5 or 6,
m, o 0, 1 or 2
mean,
as well as their physiologically acceptable salts and solvates. 2. Compounds of formula I according to claim 1

• a) 5- [N '- (3-guanidino-benzoyl) hydrazino] -5-oxo-3-phenylpentanoic acid,
• b) 3- [4- (3-guanidino-phenylacetyl) semicarbazido] -3-phenyl propionic acid,
• c) 3- [4- (3-guanidinobenzoyl) semicarbazido] -3-phenyl-propionic acid,
• d) 4- {N '- [5- (4-methyl-pyridin-2-ylamino) pentanoyl] hydrazinocarbonyl} -3-phenylbutyric acid,
• e) 3- [4- (5-guanidino-pentanoyl) semicarbazido] -3-phenyl-propionic acid,
• f) 4- [N '- (5-guanidino-pentanoyl) hydrazinocarbonyl] -3-phenyl butyric acid,
• g) 3- [4- (3-guanidinobenzoyl) semicarbazido] -3- (4-chlorophenyl) propionic acid,
• h) 3- {4- [5- (4-methyl-pyridin-2-ylamino) pentanoyl] semicarbazido} -3- (4-chlorophenyl) propionic acid,
• i) 3- [4- (5-guanidinopentanoyl) semicarbazido] -3- (4-chlorophenyl) propionic acid,
  as well as their physiologically acceptable salts or solvates.

3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

• a) for the preparation of a compound of the formula I in which Z is NR ² , a compound of the formula II,
  in which X, Y, R ¹ and R ^{2 have} the meanings given in claim 1, and in which free amino groups are protected by a suitable amino protecting group,
  with a compound of formula III
  in which R ² and R ^{3 have} the meanings given in claim 1 and in which a free hydroxyl group is protected by a suitable hydroxyl protective group or is bound to a solid phase,
  implements
  and then removing the protecting groups and / or the solid phase,
  or
• b) a compound of the formula IV,
  in which X and Y have the meanings given in claim 1, and in which free amino groups are protected by a suitable amino protecting group,
  with a compound of formula V
  in which R ¹ , R ² , R ³ and Z have the meanings given in claim 1, and in which a free hydroxyl group is protected by a suitable hydroxyl protective group or is bound to a solid phase,
  implements
  and then removing the protecting groups and / or the solid phase; or
• c) liberates a compound of formula I from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  and / or that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.

4. Compounds of formula I according to claim 1 and their physiological harmless salts or solvates as therapeutic agents.   5. Compounds of formula I according to claim 1 and their physiological harmless salts or solvates as integrin inhibitors. 6. Compounds of formula I according to claim 1 and their physiological harmless salts or solvates for use in combating of diseases. 7. Pharmaceutical preparation characterized by a content of at least one compound of formula I according to claim 1 and / or one of their physiologically acceptable salts or solvates. 8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates for their manufacture a pharmaceutical preparation. 9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates for their manufacture a pharmaceutical preparation to combat thrombosis, Heart attack, coronary artery disease, arteriosclerosis, Inflammation, tumors, osteoporosis, infections and restenosis after Angioplasty. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates pathological processes that entertain through angiogenesis or be propagated.